KR20150070042A - Use of HLA-B*1301 allele - Google Patents

Abstract

The present invention discloses the use of the HLA-B * 1301 allele comprising 1) and 2): 1) the manufacture of a product for assessing the risk of adverse drug reactions to an individual in a person. The use of a substance to detect whether it has the B * 1301 allele; 2) a method for detecting or assessing the risk of a drug adverse reaction to Dapson in an individual comprising detecting whether the individual has the HLA-B * 1301 allele, wherein the individual having the HLA-B * 1301 allele B * 1301 allele on both chromosomes of a pair of homologous chromosomes, compared with individuals without the HLA-B * 1301 allele, suffering from a higher risk of adverse drug reactions to Dapson upon administration of Dapson Individuals carrying the gene suffer from a higher risk of adverse drug reactions to Dapson when administered to Dapson compared to individuals carrying the HLA-B * 1301 allele on only one of the pair of homologous chromosomes. Way.

Description

Use of the HLA-B * 1301 allele [Use of HLA-B * 1301 allele]

The present invention relates to the use of the HLA-B * 1301 allele as a genetic marker of the use of the HLA-B * 1301 allele, particularly the risk of dapsone syndrome.

MHC (major histocompatibility complex) is a gene complex associated with graft rejection. Human MHC is referred to as HLA (human leukocyte A system). The abundant polymorphism is an essential feature of the HLA gene system. In the human population, there are many variants of the DNA sequences within the gene locus in many HLA complexes, the variants of which are called alleles. The HLA allele system is located on chromosome 6. Since humans are randomly crossed heterozygous populations, it is unlikely that the two HLA alleles in each individual are completely identical, as it not only makes HLA the system with the most abundant polymorphism in the human body, but also the HLA allele And the product of which is a biological "identification card" of the specificity retained by the individual, ie a marker of personality. The polymorphism of the HLA system ensures the appropriate immune response of the population to a variety of pathogens to ensure group continuity and to maintain its stability. Many HLA molecules have been found to be involved in drug responses in different populations. For example, the HLA-B * 1502 allele in the Chinese and Thai populations, or the HLA-A * 3101 allele in the white and Japanese populations is associated with drug hypersensitivity reactions resulting from carbamazepine; In the white population, the HLA-B * 5701 allele is associated with a drug response resulting from avacavir; In the Chinese population, the HLA-B * 5801 allele is associated with a drug response resulting from allopurinol. However, to date, no drug response has been found to be due to the HLA-B * 1301 allele, which has previously been reported to have been associated with allergic dermatitis resulting from trichlorethylene (industrial solvents) (Li H, Dai Y, Huang H, et al. HLA-B * 1301 as a biomarker for genetic susceptibility to hypersensitivity dermatitis induced by trichlorethylene among workers in China Environ Health Perspect 2007;

Dapson (4,4'-diaminodiphenylsulfone, DDS) synthesized in 1908 is anti-infective and anti-inflammatory. Alone or in combination with other drugs, the drug is characterized by the treatment of infectious diseases (such as leprosy, malaria, diseases induced by actinomycetes infection, and alveolar pneumonia due to HIV infection), or abnormal infiltration of neutrophils or eosinophils Chronic inflammatory diseases such as autoimmune bullous disease, persistent uplift erythema, pustular psoriasis, gibberellic acidosis, acne). In addition, the drug can further provide treatment to treat rheumatoid arthritis, while at the same time protecting the nerves of patients with acute ischemic stroke to a certain degree.

Previous epidemiological studies have shown that about 0.5-3% of patients treated with DDS can suffer from drug hypersensitivity syndrome with a mortality rate of about 11-13%. In early 1949, Lowe was aware of this phenomenon; The disease was officially named in 1951 as "Dapserson Syndrome Syndrome (DHS)". DHS, a serious heterozygote for an individual to the drug, has been shown to be 4-6 after DDS treatment, accompanied by clinical signs including high fever, rash and intestinal involvement (typically liver and blood system involvement), and even severe It usually happens within a week. Combination of leprosy With the worldwide use of DDS for the chemoprevention of chemotherapy and the prevention of pneumonia caused by HIV infection, the incidence of DHS is significantly increased. A recent systematic review of published epidemiological studies summarizes that the prevalence of DHS is approximately 1.4%. However, to date there are no reliable detection methods available for predicting the risk of DHS.

The technical problem to be solved by the present invention is to provide a novel use of the HLA-B * 1301 allele as a genetic marker of the risk of Dapson's syndrome.

A novel use as provided by the present invention is at least one of the following:

1) the use of a substance to detect whether an individual has an HLA-B * 1301 allele in the manufacture of a product for detecting or assessing the risk of adverse drug reaction to Dapson in an individual;

2) the use of a substance to detect whether an individual has an HLA-B * 1301 allele in the manufacture of a product for the purpose of detecting or assessing the risk of a risk of Dapserson's Syndrome Syndrome in an individual;

3) the use of a substance to detect whether an individual has an HLA-B * 1301 allele in the manufacture of a product for screening for a disorder of hypersensitive syndrome;

4) A method for detecting or evaluating the risk of a drug adverse reaction to Dapson in an individual comprising detecting whether the individual has the HLA-B * 1301 allele, wherein the individual having the HLA-B * 1301 allele Is associated with a higher risk of adverse drug reactions when using Dapson compared to individuals without the HLA-B * 1301 allele, and individuals with HLA-B * 1301 alleles on both chromosomes of a pair of homologous chromosomes Wherein the use of Dapson suffers from a higher risk of adverse drug reactions when compared to an individual holding the HLA-B * 1301 allele on only one of the pair of homologous chromosomes;

5) A method for detecting or assessing the risk of developing a disorder of susceptibility syndrome in an individual comprising detecting whether the individual has the HLA-B * 1301 allele, wherein the individual having the HLA-B * 1301 allele is HLA Individuals who suffer from a higher risk of Dapsor's Syndrome Syndrome when using Dapson compared to individuals without the -B * 1301 allele and who have the HLA-B * 1301 allele on both chromosomes of a pair of homologous live organisms Wherein one of the pair of homologous chromosomes suffers from a higher risk of hypersensitivity syndrome when using Dapson compared to an individual carrying the HLA-B * 1301 allele;

6) a method developed to treat adverse drug reactions to Dapson, including identifying and / or screening candidate drugs with a detection method using the HLA-B * 1301 allele as a target;

7) a method developed to treat the disorder-related hypersensitivity syndrome, comprising identifying and / or screening candidate drugs with a detection method using the HLA-B * 1301 allele as a target;

8) A product for detecting or evaluating the risk of an adverse drug reaction to a Dapson in an individual comprising a substance for detecting whether an individual has an HLA-B * 1301 allele.

Substances for detecting whether an individual has the HLA-B * 1301 allele in 1), 2), 3) and 8) above may be any method for measuring the presence of alleles as known in the art Kit, and / or device used in the < / RTI > For example, reagents, kits and / or devices can be used to detect the presence of an HLA-B * 1301 allele by at least one of HLA serotype crystals as well as DNA-specific hybridization, PCR-based HLA sequence typing, . ≪ / RTI > Here, the PCR primers used in the PCR-based HLA sequence-type crystallization can be specifically primer pair 1 and / or primer pair 2. Wherein said primer pair 1 consists of single-stranded DNA as set forth in SEQ ID NO: 1 and SEQ ID NO: 2; Primer pair 2 consists of single-stranded DNA as set forth in SEQ ID NO: 3 and SEQ ID NO: 4. In one embodiment of the invention, the substance for detecting whether an individual has the HLA-B * 1301 allele in 1), 2), 3) and 8) is primer pair 1 and / or primer pair 2, Or the primer pair 1 and / or the primer 2.

The substance for detecting whether an individual has an HLA-B * 1301 allele in the above 1), 2) 3) and 8) is further characterized in that the presence of the individual is indicative of the presence of an HLA- Kit and / or device used in the method for detecting whether or not the B * 1301 allele has an equivalent genetic marker of the B * 1301 allele. The presence of an HLA-B * 1301 allele in the above 4) and 5) means that the presence of the HLA-B * 1301 allele is indicative of the presence of the HLA-B * 1301 allele Can be further measured. An equivalent genetic marker is a genetic marker linked to the HLA-B * 1301 allele. Equivalent genetic markers include single nucleotide polymorphism (abbreviated as SNP), single sequence repeat (SSR) markers,

In fact, the Genome Sequencer FLX system developed by Roche 454 Life Sciences and PCR-SSOP-Luminex (the main device is Luminex 100, 200, 3D flow Luminexs from US Luminex Corporation), PCR-SSP, Sanger sequencing Second-generation sequencing analyzers such as 3130, 3130XL, 3730, 3730XL) can be used to detect whether an individual has the HLA-B * 1301 allele.

In 1), 2), 3) and 8), the product may be a reagent or a kit, or a reagent or a combination of a device and a kit.

Detection of whether an individual has an HLA-B * 1301 allele in the above 4) and 5) includes detecting alleles known in the art, such as DNA-specific hybridization, PCR-based HLA sequenced and / or HLA serotype determinations Any method for measuring the presence can be applied.

In this application, it may be used to detect whether an individual has DNA, RNA, protein, cell or serum prepared from the peripheral blood of the individual to be detected, whether or not the individual has the HLA-B * 1301 allele.

In particular, in 6) and 7) above, the isolated cells expressing the HLA-B * 1301 allele may be contacted with the drug to be tested and thereafter tend to inhibit the expression and / or function of the HLA-B * 1301 allele , Is used as a candidate drug to further test its efficacy to treat adverse drug reactions to Dapson, such as Dapson's hypersensitivity syndrome.

Such adverse drug reactions are unwanted and unintended drug effects, such as adverse reactions occurring in doses to prevent, diagnose or treat the disease. If a patient is more likely to develop a drug-induced adverse reaction than the general population, the patient will be at risk of developing a drug-related adverse reaction.

In one embodiment of the invention, the results of a study performed on a group of 76 DHS patients and 1034 non-DCHS clinical controls showed that individuals with one HLA-B * 1301 allele (a pair of homologous chromosomes Had an HLA-B * 1301 allele), the risk of DHS was 37.53-fold compared to individuals without the HLA-B * 1301 allele after DDS administration (confidence level, 0.95; confidence interval, , 74.94)); Individuals with two HLA-B * 1301 risk alleles (carrying the HLA-B * 1301 allele on either pair of homologous chromosomes), compared to individuals without the HLA-B * 1301 allele after DDS administration The risk of DHS is 110.8 times (confidence level, 0.95; confidence interval, (25.85, 474.54)).

Figure 1 shows the correlated signals of the HLA region.
A shows that HLA- B * 1301 (shown as an arrow) is the most significantly related allele in the MHC region. The recombination rate is expressed in a light blue peak shape. SNPs, alleles, and amino acids as introduced are indicated by circles, and labeled SNPs are denoted by a dashed line. Different colors express the degree of correlation of these SNPs, alleles and amino acids with the HLA-B * 1301 locus. Red, correlation coefficient>0.8; Orange, correlation coefficient = 0.5-0.8; Yellow, correlation coefficient = 0.2-0.5; Gray, correlation coefficient <0.2; And white, correlation coefficient = 0.
B shows a correlated signal chart in the MHC region after status analysis by controlling the HLA-B * 1301 locus; No residual correlated signals were observed, demonstrating that only one individual signal, HLA-B * 1301, is present in this region.
Figure 2 is a receiver operating characteristic curve for a risk prediction performed on DHS using HLA-B * 1301 as a predictive marker.

The following examples, which are not intended to limit the invention, serve to provide a better understanding of the present invention. All experimental methods used in the following examples are conventional unless otherwise indicated.

All materials, reagents and the like used in the following examples are commercially available unless specifically indicated.

Example 1. The HLA-B * 1301 allele is a genetic marker of Dapson's hypersensitive syndrome.

I. Sample

Samples containing case samples, clinical control samples and healthy control samples were peripheral blood from humans.

1. Case sample

76 Chinese DHS patients (39 for discovery-phase studies, and 37 for validation-phase studies) were included in the study. These 76 patients received DDS when they received combination chemotherapy for leprosy. The male to female ratio was 1.6: 1 in the patient group with an average age of 38 years. It took 2-8 weeks (mean 32.79 days) from the initial administration of DDS to the occurrence of DHS clinical symptoms. The most common skin lesions were spot dermatitis (57.7%), second case of withdrawal dermatitis (38.5%), scarlet fever erythema (7.7%) and oral erosion (1.3%). Systemic symptoms included: fever (83.1%), abnormal liver function (74.4%), and swollen lymph nodes (34.6%). Laboratory results showed an abnormal increase in serum hepatic enzyme levels: a significant increase in levels of alanine transaminase in 58 patients and a significant increase in levels of aspartate aminotransferase in 49 patients 37 patients had decreased levels of hemoglobin, and 35 patients had abnormally elevated levels of serum bilirubin. Diagnosis of DHS was based on patient history, clinical signs and laboratory tests.

2. Clinical control samples

Clinical control samples of the study included 1034 non-DCHS patients (833 for the discovery phase, and 201 for the verification phase). Each of these 1034 non-DHS patients was leprosy and received DDS as part of a combination chemotherapy regimen for the treatment of leprosy and no clinical symptoms or abnormal biological indicators of DHS were observed in any of these clinical control samples I did.

These clinical control samples and case samples were generally geographically and ethnically compatible.

3. A healthy control sample

In the study, healthy control samples included 1944 healthy control samples to assess HLA-B * 1301 frequency in the Chinese population, including 951 samples in Guangdong, 523 samples in Shandong, and 470 samples to be.

Diagnosis of patients with leprosy was established on the basis of two or more of the following four criteria: 1. Peritoneal and ischidrosis, or skin lesions associated with the paralysis; 2. nerve involvement marked as a thick nerve stem associated with the corresponding disorder; 3. nabyeonggyun (Mycobacterium leprae) are cross-sectional tissue of the skin lesions and Detected in tissue latex smears; 4. Pathologically visible changes in character.

Diagnostic criteria for healthy controls: no history of leprosy and other infectious diseases, and no history or family history of other autoimmune diseases.

II. Way

1. Discovery phase

Genotyping was performed on 833 non-DHS patients in 39 DHS patients and clinical control samples in case samples using the Illumina-660 chip (Illumina Human 660W-Quad beadchip). A total of 430,276 SNPs from 39 DHS patients and 833 non-DHS patients were used for data analysis at the discovery stage of the genome-wide scan.

Using the Asian HAPMAP (International HapMap Project) reference sequence (a total of 178 individuals, including Han Chinese migrants from Beijing, Chinese from Japan, and Japanese), 833 non-responders from 39 DHS patients and clinical control samples from case samples, For each individual of DHS patients, an import analysis of HLA alleles (dichotomous and quartiles) and amino acids was performed and a total of 66 typical HLA dichotomized alleles, 118 typical quadratic HLA alleles, 497 Polymorphic amino acid positions and 4206 SNPs were introduced and applied to the correlation analysis together with 4636 SNPs obtained from the classification. As shown in the results of the correlation analysis (A in FIG. 1), a single nucleotide polymorphism site (physical distance of 26,000,000-34,000,000) located in the MHC region of the sixth chromosome (NCBI bulid 37) Dapserson hypersensitivity syndrome.

Logistic regression analysis was performed on this region to define signals positively correlated in the HLA-B * 1301 and HLA-C * 0304 loci. The correlation coefficient between these two loci was 0.74. In addition, a correlation analysis performed on weakly expressed HLA-B * 13 dichleric alleles and 497 polymorphic amino acid positions indicates that each of the signals is more sensitive than that of HLA-B * 1301 Respectively. No other independent signal was observed in the MHC region when HLA-B * 1301 was controlled (Figure 1B). Briefly, it was demonstrated that HLA-B * 1301 was the major allele of DHS risk. HLA-B * 1301 (P = 2.04 x 10 ^-16 ; OR = 21.67, confidence level, 0.95, confidence interval (10.41, ).

2. Verification step

In order to further confirm the correlation of the HLA-B * 1301 allele, a 454 sequence analysis platform (Genome Sequencer FLX system developed by Roche 454 Life Sciences) was used to compare the sample samples from 37 other DHS patients and clinical control samples HLA classification was performed on another 201 non-DHS patients (randomly selected from a total of 1089 validation controls). Here, PCR amplification was performed on genomic DNA isolated from the peripheral blood of samples for the HLA-B * 1301 allele using primer pair 1 and primer pair 2, respectively. Primer pair 1 consists of single-stranded DNA as set forth in SEQ ID NO: 1 and SEQ ID NO: 2; Primer pair 2 consists of single-stranded DNA as set forth in SEQ ID NO: 3 and SEQ ID NO: 4.

Recall of HLA allele was performed in GATK using HLA Caller software and subsequent correlation analysis was performed by logistic regression method. The results were HLA- B * 1301 (OR = 23.54, confidence level, 0.95, confidence (8.71, 63.62); P = 4.74 x 10 ^-10 ).

3. Combination analysis

The HLA-B * 1301 allele was found to be DHS: (OR = 22.32, confidence level, 0.95, confidence interval, (12.40, 40.28); P = 6.32 x 100 ^-25 ) And that it is strongly associated with.

Using the 454 sequencing platform (Genome Sequencer FLX system developed by Roche 454 Life Sciences), HLA classifications were performed on 1034 DHS patients and 1034 non-DHS patients in 76 sample DHS patients and clinical control samples, Are shown in Table 1 below.

Table 1. HLA classification results

Note: In the first column, N represents the total number of samples; In columns 2 and 3, numerical values outside parentheses indicate the number of samples, and the percentages in parentheses indicate the ratio of numerical values outside the parentheses to the total number of samples.

As shown in Table 1, 66 false positive samples (HLA-B * 1301 retainers) among the 76 DHS patients were false negative samples (non-HLA-B * 1301 holders) were 10; Among 1034 non-DHS patients, the number of intrinsic negative samples (non-HLA-B * 1301 retainers) was 886 and the number of positive samples (HLA-B * 1301 retainers) was 148. Using HLA-B * 1301 as the predictive marker, the risk prediction performed for DHS had a sensitivity of 86.84% and a specificity of 85.69% (Figure 2), where sensitivity = true positive sample / (number of intact positive samples + Number of false negative samples) x 100%, specificity = number of true positive samples / (number of true negative samples + number of false positive samples) x 100%. HLA-B * 1301 heterozygous holders were at risk for DHS at OR _het = 61 x 886/10 x 144 = 37.53 (confidence level, 0.95; confidence interval (18.80, 74.94)); HLA-B * 1301 homozygous holders were at risk for DHS at OR _hom = 5 x 86/10 x 4 = 110.75 (confidence level, 0.95; confidence interval (25.85, 474.54)). As can be seen, the HLA- B * 1301 allele was retained by 86.8% (66/76) of DHS patients and only 14.3% (148/1034) of non-DHS patients. As shown by the results, when the individual had one HLA-B * 1301 risk allele (HLA-B * 1301 heterozygous retainer), after DDS administration, the individual was free of the HLA-B * 1301 allele (Confidence level, 0.95; confidence interval, 18.8, 74.9); When an individual has two HLA-B * 1301 risk alleles (HLA-B * 1301 homozygous retainers), after DDS administration, the individual has 110.8-fold higher DHS (Confidence level, 0.95; confidence interval (25.9, 474.5)).

A recent review of Asian populations estimated the prevalence of DHS to be 1.4% (Lorenz, Wozel et al. 2012). Based on this prevalence, the positive predictive value was 7.9%, the negative predictive value was 99.8%, the likelihood ratio was 6.07, and the negative likelihood ratio was 0.1536. According to the positive likelihood ratio of 6.07, the risk of DHS in individuals with HLA-B * 1301 increased to 7.9%; According to the negative likelihood ratio of 0.1536, the incidence of DHS in individuals with HLA-B * 1301 decreased from 1.4% to 0.2%. Screening for the HLA-B * 1301 allele performed on patients requiring DDS treatment showed that the incidence of DHS in the positive holders could be greatly reduced from 1.4% to 0.2% without the administration of the drug.

Results from 1944 healthy controls in healthy control samples (from Shandong, Guangdong and Panzan) indicated that the HLA-B * 1301 allele had a frequency of 3.3% in the Shandong sample, a frequency of 7.1% in the raw sample, The frequency of the HLA-B * 1301 allele in the North Chinese population (2-5%) and the frequency of the allele frequency in the South Chinese population (5-20%) was 8.2% Consistent with those reported in the database. Taking into account the relative prevalence of these loci in not only Asian countries but also Chinese populations, HLA-B * 1301 screening and risk assessment before administration of DDS will have significant benefits.

Industrial application

Indeed, the presence or absence of the HLA-B * 1301 allele may be detected to predict whether DHS will develop in a patient in need of DDS therapy. The risk prediction can be made based on the detection result. Individuals with HLA-B * 1301 are suggested to be treated with other drugs instead of DDS therapy, which may result in drug hypersensitivity reactions. Individuals without HLA-B * 1301 are safe to use DDS because DDS treatment will result in drug hypersensitivity with a very low probability.

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Claims (11)

Use of a substance for the detection of an individual having an HLA-B * 1301 allele in the manufacture of a product for detecting or evaluating the risk of adverse drug reactions to Dapson in an individual. The use according to claim 1, characterized in that the adverse drug reaction to Dapson is Dapson's hypersensitivity syndrome. 3. Use according to claim 2, characterized in that the substance for detecting whether an individual has the HLA-B * 1301 allele is the following a) and / or b):
a) reagents, kits and / or devices used to measure the presence of the HLA-B * 1301 allele by at least one of the DNA-specific hybridization, PCR-based HLA sequence type crystals as well as HLA serotype crystals;
b) determining whether the individual has an equivalent genetic marker of the HLA-B * 1301 allele, wherein the presence of an equivalent genetic marker of the HLA-B * 1301 allele is indicative of the presence of the HLA-B * Reagents, kits and / or devices used in the method for detection. Use of a substance to detect whether an individual has an HLA-B * 1301 allele in the manufacture of a product for screening for Dapson's Syndrome Syndrome. 5. Use according to claim 4, characterized in that the substance for detecting whether an individual has the HLA-B * 1301 allele is / a) and / or b)
a) reagents, kits and / or devices used to measure the presence of the HLA-B * 1301 allele by at least one of the DNA-specific hybridization, PCR-based HLA sequence type crystals as well as HLA serotype crystals;
b) determining whether the individual has an equivalent genetic marker of the HLA-B * 1301 allele, wherein the presence of an equivalent genetic marker of the HLA-B * 1301 allele is indicative of the presence of the HLA-B * Reagents, kits and / or devices used in the method for detection. A product for detecting or assessing the risk of an adverse drug reaction to a Dapson in an individual comprising a substance for detecting whether an individual has an HLA-B * 1301 allele. 7. Use according to claim 6, characterized in that the substance for detecting whether an individual has an HLA-B * 1301 allele is the following a) and / or b):
a) reagents, kits and / or devices used to measure the presence of the HLA-B * 1301 allele by at least one of the DNA-specific hybridization, PCR-based HLA sequence type crystals as well as HLA serotype crystals;
b) determining whether the individual has an equivalent genetic marker of the HLA-B * 1301 allele, wherein the presence of an equivalent genetic marker of the HLA-B * 1301 allele is indicative of the presence of the HLA-B * Reagents, kits and / or devices used in the method for detection. A method for detecting or assessing the risk of adverse drug reactions to Dapson in an individual, said method comprising the step of detecting whether the individual has an HLA-B * 1301 allele, wherein the HLA-B * Individuals with the 1301 allele suffer from a higher risk of adverse drug reactions to Dapson when administered with Dapson compared to individuals without the HLA-B * 1301 allele, Individuals carrying the -B * 1301 allele have a higher risk of adverse drug reactions to Dapson when compared to individuals with the HLA-B * 1301 allele on only one of the pair of homologous chromosomes How to suffer. 9. The method of claim 8, wherein the adverse drug reaction to Dapson is Dapson's Syphilis Syndrome. Comprising identifying and / or screening a candidate drug with a detection method using the HLA-B * 1301 allele as a target. Comprising identifying and / or screening a candidate drug with a detection method using the HLA-B * 1301 allele as a target. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

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